Cofilin Signaling in Hemorrhagic Stroke

出血性中风中的 Cofilin 信号转导

基本信息

批准号：
10598544
负责人：
Zahoor Ahmad Shah
金额：
$ 40.1万
依托单位：
UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-15 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10598544
关键词：
Actin-Binding Protein Actins Address Alzheimer&apos s Disease American Animals Area Autologous Autopsy Behavioral Binding Biological Assay Blood brain barrier dysfunction Brain Brain Injuries Brain hemorrhage Case Study Cause of Death Cell Death Cells Central Nervous System Cerebral hemisphere hemorrhage Corpus striatum structure Crossbreeding Cytoskeletal Proteins Disease Enterobacteria phage P1 Cre recombinase F-Actin Female Filament Functional disorder Hematoma Hemin Human Immune Immunofluorescence Immunologic Impaired cognition In Vitro Inflammation Injections Injury Ischemic Stroke Knock-out Knockout Mice Left Lipopolysaccharides Maps Mediating Mediator Microfilaments Microglia Modality Modeling Morbidity - disease rate Motor Mus Neurites Neurodegenerative Disorders Neuronal Injury Neurons Operative Surgical Procedures Outcome PTGS2 gene Pathologic Pathway interactions Pattern Phase Pilot Projects Play Prevalence Process Protein Isoforms Publishing Recovery Risk Rod Role Sex Differences Signal Transduction Site Small Interfering RNA Specimen Stress Stroke Survivors Synapses TNF gene Tail Testing Therapeutic Therapeutic Agents Therapeutic Studies Time Veins Whole Blood Wild Type Mouse actin depolymerizing factor aged analog calmodulin-dependent protein kinase II cofilin cofilin 2 disability drug development drug discovery effective therapy experimental study functional disability glial activation improved inhibitor insight male migration mortality mouse model neurobehavioral neuroinflammation neuron loss new therapeutic target novel novel therapeutic intervention post stroke cognitive impairment promoter public health relevance spatiotemporal stroke cognitive outcome stroke therapy targeted treatment translational potential

项目摘要

Hemorrhagic stroke constitutes only 10-15% of total stroke types but is responsible for higher mortality rates and survivors suffer from severe disabilities and post-stroke cognitive impairments (PSCI). Except for surgical intervention, there is no effective treatment for intracerebral hemorrhage (ICH). In order to develop effective treatment modalities, it is imperative to gain a better understanding of the pathways that are active after ICH, in particular, during secondary injury involving microglial activation mediated neuroinflammation and PSCI. Microglia play an important role responding to injuries in the brain and a comprehensive understanding of the microglia-specific signaling during episodes of injury are pivotal for mitigating the damage induced by ICH. The three cofilin isoforms: actin binding protein, cofilin1 (cofilin) and cofilin2 are important regulators of F-actin turnover and reorganization and alterations in these processes can lead to neurodegenerative diseases. Cofilin rods/aggregates formed during pathological conditions play a crucial role in microglial activation, synaptic dysfunction and neuronal death. As a mechanistic proof of concept, targeting cofilin with siRNA or inhibitor in mice led to decreased hematoma volume, improved neurobehavioral functions and PSCI after experimental ICH. Immunofluorescence analysis of human autopsy ICH brain specimens also showed widespread cofilin activation in microglia in the perihematoma area. The novel findings support the scientific premise that cofilin signaling plays a key role in the secondary phase of ICH involving microglial activation and inflammation and subsequent PSCI and led us to hypothesize that inhibition of cofilin presents a novel therapeutic strategy. The proposed hypothesis will be addressed in three aims. Aim 1 will identify cofilin rods/aggregates and microglial activation in human ICH autopsy brain specimens by performing immunofluorescence. The spatiotemporal pattern of cofilin rods/aggregates and PSCI will be determined in wildtype (WT) mice over a protracted period of 60 days following ICH. Aim 2 will identify whether microglial or neuronal cofilin is mediating neuroinflammation and PSCI after ICH by using neuron and microglia-specific cofilin knockout mice. Aim 3 will study the therapeutic potential of a novel first of its class, cofilin inhibitor in aged WT mice subjected to ICH. The studies outlined in this proposal will provide insights on the role of cofilin signaling in ICH induced-microglial activation, inflammation and PSCI and the identification of potential therapeutic agents for drug discovery and development.

出血性中风仅占所有中风类型的 10-15%，但却导致较高的死亡率率和幸存者患有严重残疾和中风后认知障碍（PSCI）。除了对于手术干预，脑出血（ICH）尚无有效的治疗方法。为了开发有效的治疗方式，必须更好地了解其途径 ICH后，特别是在涉及小胶质细胞激活介导的继发性损伤期间，这些细胞是活跃的神经炎症和 PSCI。小胶质细胞在应对大脑损伤和全面了解损伤期间小胶质细胞特异性信号传导对于减轻ICH引起的损害。三种 cofilin 亚型：肌动蛋白结合蛋白、cofilin1（cofilin） cofilin2 和 cofilin2 是 F-肌动蛋白周转、重组和这些变化的重要调节因子。过程可能导致神经退行性疾病。病理过程中形成的 Cofilin 棒/聚集体条件在小胶质细胞激活、突触功能障碍和神经元死亡中起着至关重要的作用。作为一个概念的机制证明，在小鼠中用 siRNA 或抑制剂靶向丝切蛋白导致减少实验性 ICH 后血肿量、神经行为功能和 PSCI 改善。人体尸检 ICH 脑标本的免疫荧光分析也显示广泛存在丝切蛋白血肿周围区域小胶质细胞的激活。这些新颖的发现支持了这样的科学前提： cofilin 信号在 ICH 的第二阶段发挥关键作用，涉及小胶质细胞激活和炎症和随后的 PSCI 使我们假设抑制 cofilin 提供了一种新的治疗策略。所提出的假设将通过三个目标来解决。目标 1 将识别肌动蛋白丝切蛋白通过执行人类 ICH 尸检脑标本中的杆/聚集体和小胶质细胞激活免疫荧光。将确定丝切蛋白棒/聚集体和 PSCI 的时空模式在野生型 (WT) 小鼠中，ICH 后持续 60 天。目标 2 将确定是否小胶质细胞或神经元丝切蛋白通过使用神经元和 ICH 介导神经炎症和 PSCI 小胶质细胞特异性丝切蛋白敲除小鼠。目标 3 将首先研究一部小说的治疗潜力类别，经受 ICH 的老年 WT 小鼠中的肌动蛋白丝切蛋白抑制剂。本提案中概述的研究将提供有关丝切蛋白信号传导在 ICH 诱导的小胶质细胞激活、炎症和 PSCI 以及用于药物发现和开发的潜在治疗剂的鉴定。